Reduction of carboxylic acids and their derivatives plays an important role in organic synthesis, both in laboratory and industrial processes. Traditionally, the reduction is performed using stoichiometric amounts of hydride reagents, generating stoichiometric amounts of waste (Seyden-Penne). A much more attractive, atom-economical approach is a catalytic reaction using H2; however, hydrogenation of carboxylic acid derivatives under mild conditions is a very challenging task (Rylander; Hartwig), with amides presenting the one of the highest challenges among all classes of carbonyl compounds. A few examples of the important hydrogenation of amides to amines, in which the C—O bond is cleaved with the liberation of water (Scheme 1), were reported (Hirosawa et al., Núñez Magro et al., Beamson et al.). This reaction can also be affected with silanes as reducing agents (Fernandes et al., Das et al.). In addition, the interesting hydrogenation of cyclic N-acylcarbamates and N-acylsolfonamides, which involves cleavage of the C—N bond, but does not form amines, was recently reported (Ito et al., 2009).
On the other hand, selective, direct hydrogenation of amides to form amines and alcohols has not been reported. Hydrogenation of amides to amines (via C—O cleavage, generating water) can have C—N cleavage as a side reaction, requiring the presence of water, and resulting from catalytic hydrolysis of the amides to acids and amines, followed by hydrogenation of the acids to alcohols: see Núñez Magro et al. and Beamson et al) However, no amide C—N hydrogenolysis to form alcohols and amines was reported in absence of water.
Amines and alcohols are used extensively in the chemical, pharmaceutical and agrichemical industries (Lawrence; Ricci; Kumara et al.). Design of such a reaction is conceptually challenging, since the first mechanistic step in amide hydrogenation is expected to be H2 addition to the carbonyl group to form a very unstable hemiaminal which, in the case of primary or secondary amides, spontaneously liberates water to form an imine; further hydrogenation of the imine then leads to amine formation (Scheme 1). For amine and alcohol formation, cleavage of the C—N bond in preference to the C—O bond is required.

The reverse reaction, i.e., amide formation from alcohols and amines with liberation of H2, was previously reported by inventors of the present invention, and later, by others (Nordstrom; Ghosh; Shimizu) Formation of amides from alcohols and amines by use of hydrogen acceptors was also reported recently (Zweifel; Watson). The importance of amides in chemistry and biology is well recognized and has been studied extensively (Sewald et al.; Greenberg et al.; Smith and March; Bray). Although several methods are known for the synthesis of amides, preparation under neutral conditions and without generation of waste is a challenging goal (Larock; Smith). Synthesis of amides is mostly based on activated acid derivatives (acid chlorides, anhydrides) or rearrangement reactions induced by acid or base which often involve toxic chemical waste and tedious work-up (Smith). Transition-metal catalyzed conversion of nitriles into amides was reported (Cobley et al.; Murahashi et al. 1986 and 1992). Catalytic acylation of amines by aldehydes in the presence of a stoichiometric amount of oxidant and a base is known (Tamaru et al., Tillack et al.). Recently, oxidative amide synthesis was achieved from terminal alkynes (Chan et al.). Cu(I) catalyzed reaction of sulfonyl azides with terminal alkynes is a facile method for the synthesis of sulfonyl amides (Cho et al.; Cassidy et al.).
Polyamides are one of the most important polymer classes, extensively used in fiber products, plastics and their derivatives, with many applications, including in biomedical studies. Recently, the synthesis of functional polyamides has received considerable attention. Generally, polyamides are synthesized by condensation of diamines and activated dicarboxylic acid derivatives and/or in the presence of coupling reagents. In some cases, ring opening of small-ring lactams at high temperatures leads to polyamides. To avoid the use of activators, waste generation, or harsh conditions, the development of economical, efficient and environmentally benign protocols are desirable.
Transition metal borohydride complexes display extensive reactivity with organic substrates and are useful starting materials for the preparation of transition metal hydrides and borides (Dick et al; White et al). They have found uses in catalytic hydroboration (Burgess et al., Isagawa et al., Lee et al); polymerization of olefins (Barbier-Baudry et al., Bonnet et al, and Marks et al.) and cyclic esters (Palard et al.). Ruthenium hydrido borohydride complexes based on bidentate phosphorus ligands and diamines, reported by Ohkuma et al, Sandoval et al. and Guo et al. are effective catalysts in asymmetric transfer hydrogenation of ketones (Ohkuma et al., Sandoval et al., Guo et al) and enantioselective Michael addition (Guo et al.). In addition, borohydride complexes may represent plausible models for CH4 coordination in the transition state for C—H activation (Jensen et al. 1986 and 1988).
Transition metal complexes of bulky, electron-rich tridentate ligands have found useful applications in synthesis, bond activation, and catalysis (see recent reviews: Van der Boom et al., Albrecht et al., Vigalok et al., Jensen 1999 and Rybtchinski et al.). The highly electron-donating tBu-PNP (2,6-bis(di-tert-butylphosphinomethyl)pyridine) and its group 8 metal complexes have been explored by several groups (Kawatsura et al., Stambuli et al., Gibson et al., and Kloek et al) as well as by some of the inventors of the present invention (Hermann et al., Ben-Ari et al. 2003 and 2006, Zhang et al. 2004, 2005 and 2006, and Feller et al).
Dehydrogenation of alcohols to carbonyl compounds without a hydrogen acceptor or oxidant, with the evolution of molecular hydrogen, is attractive economically and environmentally (Scheme 2), but homogeneous systems capable of thermally catalyzing dehydrogenation of alcohols are relatively rare (Zhang et al. 2004 and 2005, Murahashi et al. 1987, Charman et al., Morton et al., Dobson et al., Jung et al., Ligthart et al., Shinoda et al., Matsubara et al., Adair et al., Lin et al. 1997 and 1992, Blum et al., and Zhao et al.).

Catalytic hydrogenation of polar carbonyl bonds is a simple, convenient, and sustainable method which plays a pivotal role in both industrial processes and academic research. The hydrogenation of esters to alcohols is an important transformation and remains a challenging task in the perspective of “green and sustainable chemistry (GSC)” where the transformation is atom-economic without generating any large amount of metal waste. Despite well-documented homogeneously catalyzed reductions of ketones and aldehydes, the catalytic hydrogenation of esters to alcohols under mild and homogeneous conditions is relatively underdeveloped, owing to the poor hydridophilicity (electrophilicity) of the ester carbonyl functionality. The common trend in the reactivity of carbonyl groups towards hydrogenation reactions is RC(O)H>RC(O) R′>>RC(O)OR′>RC(O)NR′.
Simple 1,2-diols, e.g., propylene glycol (PG) and ethylene glycol (EG), are utilized as high value-added specialty chemical intermediates, in the manufacture of biodegradable polyester fibers, unsaturated polyester resins, antifreeze, pharmaceuticals and other important products. Currently, these two vicinal diols are industrially produced from petroleum-derived propylene and ethylene via hydration of their corresponding epoxy alkanes. However, as crude oil resources become limited, substitutes for petroleum feedstocks are increasingly sought after, and as such the synthesis 1,2-diols, indirectly from biomass derived resources is of great interest. Alternative methods which proceed under mild reaction conditions with stable and easy-to-handle homogeneous catalysts and environmentally benign are desirable.
Glycolide and lactide are important classes of cyclic di-esters (di-lactones) utilized as starting materials for Lewis-acid catalyzed polymerization reactions to synthesize biodegradable polymers. Since these compounds are produced from biomass derived resources such as glycolic acid (derived from sugar cane) and lactic acid (from fermentation of glucose) respectively via self-esterification, their efficient hydrogenation can provide alternative, mild approaches to the indirect transformation of biomass to important synthetic building blocks. Although few catalytic hydrogenations of (mono lactones) to diols are known in the literature, the complete hydrogenation of cyclic di-esters to the corresponding 1,2-diols (e.g. ethylene glycol and propylene glycol) is extremely difficult due to presence of two ester moieties and the chelating ability of the final product, 1,2-diol, which may retard the catalytic activity of the catalyst. Indeed, to the applicant's best knowledge, catalytic hydrogenation of these important families of cyclic di-esters has never been reported, be it under heterogeneous or homogeneous catalysis.
The applicants of the present invention have recently reported on new catalytic reactions of alcohols, such as dehydrogenative coupling of primary alcohols to esters and dehydrogenation of secondary alcohols to ketones using pyridine-based pincer complexes (Zhang et al. 2004, 2005, 2006 and 2007; Gunanathan 2007; Gnanaprakasam and Milstein) and acridine (Gunanathan 2008 and 2009). The catalytic efficiency of the reaction of the conversion of primary alcohols to ester was enhanced with Ru(II) complexes of an analogous ligand having a potentially “hemilabile” amine “arm”, PNN (2-(di-tert-butylphosphinomethyl)-6-(diethylaminomethyl)pyridine). (PNN)Ru(II) complexes effectively catalyze the acceptorless dehydrogenation of primary alcohols to the corresponding esters and molecular hydrogen in high yields and turnover numbers, in the presence of a catalytic amount of base. Mechanistic studies of this reaction have led to the discovery of a PNN Ru hydrido carbonyl complex, which does not require the presence of base, the catalytic reaction proceeding very effectively under neutral, mild conditions (Zhang et al. 2005).
The pyridine-based PNN Ru complex 1 (FIG. 1A) efficiently catalyzes the dehydrogenative coupling of alcohols to form esters (Zhang 2005, Zhang 2007 and Milstein), the hydrogenation of esters to alcohols under mild conditions (Zhang 2006 and Milstein) and the coupling of alcohols and amines to form amides and H2 (Gunanathan 2007 and Milstein). The PNP complex 2 (FIG. 1A) is an efficient catalyst for the dehydrogenative coupling of alcohols and amines to form imines (Gnanaprakasam 2010 and Milstein). Complex 1 is also effective in N—H activation (Khaskin et al.) and in the unique light induced splitting of water to H2 and O2 (Kohl et al.).
US patent publication no. US 2009/0112005, to some of the inventors of the present invention, describes methods for preparing amides, by reacting a primary amine and a primary alcohol in the presence of Ruthenium complexes, to generate the amide compound and molecular hydrogen.
PCT patent publication no. WO 2010/018570, to some of the inventors of the present invention, describes methods for preparing primary amines from alcohols and ammonia in the presence of Ruthenium complexes, to generate the amine and water.
Zeng et al., published after the priority date of the present application, describes a process for preparation of polyamides via catalytic dehydrogenation of diols and diamines using PNN pincer ruthenium complexes.
Given the widespread importance of amines, alcohols, amides and esters in biochemical and chemical systems, efficient syntheses that avoid the shortcomings of prior art processes are highly desirable.